Metabolic Effects of the Biguanides and Possible Mechanism of Action

Jangaard, N. O.; Pereira, J. N.; Pinson, Rex

doi:10.2337/diab.17.2.96

Cited by 41 publications

(18 citation statements)

References 8 publications

(11 reference statements)

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“…1 ' 10 Finally, biguanides have been found to affect certain metabolic events in peripheral tissues, such as an increase in the utilization of glucose 11 ' 12 or an inhibition of some steps in oxidative metabolism. 8 Our results (described below) do not support the first two hypotheses. The intestinal absorption and liver metabolism do not seem to be the decisive site of From the Department of Pharmacology, Chemische Fabrik von Heyden, Postfach 177, 84 Regensburg, Germany.…”

contrasting

confidence: 77%

Effect of Phenformin in Hyperglycemic Rats

Poláček¹,

Ouart²

1974

Diabetes

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Phenformin administered intraperitoneally in doses of 30 and 100 mg. per kilogram significantly reduced the blood glucose concentration in streptozotocin-diabetic rats, but was virtually inactive in normal healthy rats. Phenformin also antagonized the hyperglycemic effect of an intravenous infusion of epinephrine in normal anesthetized rats and decreased blood glucose concentration of hepatectomized rats infused with glucose. These results are not consistent with hypotheses explaining the biguanide effect as an impairment of the intestinal absorption of sugars and indicate that the liver is not the only site of its action. DIABETES 2J:25-28, January, 1974.Several hypotheses have been put forward to explain the hypoglycemic action of biguanides, but none has met with general approval. The subject has been reviewed many times in detail. 1 ' 3 Broadly speaking, the hypotheses can be divided into three groups. One group of investigators believes that the biguanides exert their therapeutic effect mainly by inhibiting intestinal transport and absorption of sugars; 4 " 6 this assumption is based on results of in vitro experiments with intestinal tissue and on the observation that biguanides influence the glucose disappearance rate after oral, but not after intravenous, administration of the sugar. Other authors place the site of action of biguanides in the liver, but results of relevant experiments are contradictory: in perfused liver and minced liver tissue, an inhibition of gluconeogenesis from various substrates was observed, 7 ' 9 whereas in vivo the reverse effect was reported. 1 ' 10 Finally, biguanides have been found to affect certain metabolic events in peripheral tissues, such as an increase in the utilization of glucose 11 ' 12 or an inhibition of some steps in oxidative metabolism. 8 Our results (described below) do not support the first two hypotheses. The intestinal absorption and liver metabolism do not seem to be the decisive site of biguanide action. We conclude that the effect of biguanides should be sought in the changed metabolism of peripheral tissue. MATERIALS AND METHODSExperiments on conscious animals. Sprague-Dawley rats of both sexes, 150 to 190 gm., were rendered diabetic by a single intravenous injection of streptozotocin, 50 mg. per kilogram (Upjohn product U-9889, batch no. 16,235), which had been dissolved in citrate buffer, pH 5.0. The animals were then fed a protein-enriched diet ad libitum and used six to seven days after having been given the streptozotocin. The rats were sorted into groups having approximately the same mean blood glucose values, each group consisting of six animals. Phenformin hydrochloride (synthesized and kindly supplied by Dr. H. Hoehn of the Chemistry Department of this Institute) was dissolved in water and injected intraperitoneally in graded doses. The controls were given corresponding volumes of water. Blood samples (0. 1 ml.) were taken from the sublingual veins before and one, three, and five hours after phenformin or water was given. The blood was immediatel...

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contrasting

confidence: 77%

Effect of Phenformin in Hyperglycemic Rats

Poláček¹,

Ouart²

1974

Diabetes

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“…In nondiabetic rat adipocytes and guinea pig fat pads, metformin added in vitro increased basal glucose oxidation in a concentration-dependent manner, with maximal effects observed at 5 mM and half-maximal effects at 0.3 mM (42,51). The maximum increase was about a doubling in glucose oxidation, and the full response was observed within 2 h of addition of the drug.…”

Section: A Klip and La Lei Termentioning

confidence: 75%

Cellular Mechanism of Action of Metformin

Klip

Leiter²

1990

Diabetes Care

215

102

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Metformin is a hypoglycemic drug effective in the treatment of non-insulin-dependent diabetes mellitus and increasingly used in Canada and Europe. Effects on intestinal glucose absorption, insulin secretion, and hepatic glucose production are insufficient to explain its hypoglycemic action, with most evidence suggesting that the major effect of the drug is on glucose utilization. In vivo and in vitro studies have demonstrated that metformin stimulates the insulin-induced component of glucose uptake into skeletal muscle and adipocytes in both diabetic individuals and animal models. This increase is more significant in diabetic than in nondiabetic animals, suggesting an enhanced action of the drug in the hyperglycemic state. The increase in glucose uptake is also reflected in an increase in the insulin-dependent portion of glucose oxidation. Potential sites of action of metformin are the insulin receptor and the glucose transporters. Although metformin increases insulin binding in various cell types, this effect is not universal and does not correlate with stimulation of glucose utilization. In contrast, direct effects of the drug on the glucose-transport system have been demonstrated. Metformin elevates the uptake of nonmetabolizable analogues of glucose in both nondiabetic rat adipocytes and diabetic mouse muscle. In the latter, the stimulatory effect of the drug is additive to that of insulin. In human and rat muscle cells in culture, metformin increases glucose-analogue transport independently of and additive to insulin, suggesting an insulin-dependent action. Most of these results suggest that the basis for the hypoglycemic effect of this biguanide is probably at the level of skeletal muscle by increasing glucose transport across the cell membrane.

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“…It has been shown that metformin has no effect on insulin secretion, although a certain quantity of endogenous insulin is a prerequisite for the therapeutic effect (1)(2)(3)(4). The antihyperglycemic action of metformin is multifactorial and has been attributed to a diminished, intestinal absorption of carbohydrates (5,6), reduced gluconeogenesis (7)(8)(9), and increased peripheral glucose uptake (10)(11)(12). The mechanism of metformin's effect to reduce peripheral insulin resistance is not understood.…”

Section: Tissue (Glut4) In Adipocyte Membrane Fractions Separated By mentioning

confidence: 99%

Association of Metformin's Effect to Increase Insulin-Stimulated Glucose Transport With Potentiation of Insulin-Induced Translocation of Glucose Transporters From Intracellular Pool to Plasma Membrane in Rat Adipocytes

et al. 1991

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To examine the cellular mechanism of the antihyperglycemic action of metformin, we studied its effect on various functional and molecular parameters involved in the pathogenesis of insulin resistance. Isolated rat adipocytes were incubated with or without metformin (1-100 micrograms/ml) for 2 h at 37 degrees C followed by an incubation with or without insulin (1.72 nM). Metformin treatment had no significant effect on basal 3-O-methylglucose uptake. In contrast, metformin increased insulin-stimulated glucose transport in a dose-dependent manner up to 43 +/- 7%. This effect was neither associated with a significant effect of metformin on trace insulin binding (1.74 +/- 0.20% without metformin vs. 1.89 +/- 0.30% with metformin; P greater than 0.05) nor with an effect of metformin on insulin-receptor kinase activity as measured by 32P incorporation into the 95,000-Mr beta-subunit of the insulin receptor and an exogenous substrate, histone 2B.(ABSTRACT TRUNCATED AT 250 WORDS)

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Metabolic Effects of the Biguanides and Possible Mechanism of Action

Cited by 41 publications

References 8 publications

Effect of Phenformin in Hyperglycemic Rats

Effect of Phenformin in Hyperglycemic Rats

Cellular Mechanism of Action of Metformin

Association of Metformin's Effect to Increase Insulin-Stimulated Glucose Transport With Potentiation of Insulin-Induced Translocation of Glucose Transporters From Intracellular Pool to Plasma Membrane in Rat Adipocytes

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